US20210024454A1 - Novel compound and pharmacetical composition for preventing or treating obesity or metabolic syndrome comprising thereof - Google Patents

Novel compound and pharmacetical composition for preventing or treating obesity or metabolic syndrome comprising thereof Download PDF

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US20210024454A1
US20210024454A1 US17/041,960 US201917041960A US2021024454A1 US 20210024454 A1 US20210024454 A1 US 20210024454A1 US 201917041960 A US201917041960 A US 201917041960A US 2021024454 A1 US2021024454 A1 US 2021024454A1
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compound
ethanol
present
phenyl
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US12065394B2 (en
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Yong Tae Kwon
Srinivasrao GANIPISETTI
Ki Woon SUNG
Eui Jung Jung
Tae Hyun BAE
Su Ran MUN
Chan Hoon JUNG
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SNU R&DB Foundation
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Protech Co Ltd
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to a novel compound which can be effectively used for preventing or treating obesity or metabolic syndrome, and a pharmaceutical composition comprising the same.
  • Obesity which was considered as a simple disease, has recently been classified as a disease, and it has been reported that obesity is associated with the onset of metabolic syndrome such as type 2 diabetes, cardiovascular diseases, and certain cancers [1].
  • Obesity is a disease that results from a combination of various causes such as socio-environmental, genetic, psychiatric and endocrine factors.
  • WHO World Health Organization
  • the worldwide prevalence of obesity has increased by double since 1980 [2], and in the United States, approximately 34% of American were obese in 2013 [3]. It is the fact that the US government uses 10% of the total national medical expenses for obesity-related health care services, campaigns, etc. every year in order to reduce socioeconomic losses caused by obesity.
  • the mechanism of drugs approved from the US FDA can be divided into three categories: inhibiting lipid absorption in the small intestine through ingested foods, reducing nutrient intake and inducing weight loss by altering the activity of the feeding center in the central nervous system of the brain to induce a fictional sense of fullness, and releasing an energy flowed into the body into a thermal energy without storing it in the form of lipid.
  • these drugs can cause side effects associated with metabolic problems such as nutritional imbalance and emotional changes such as lethargy and depression [6].
  • the best way for the treatment and prevention of obesity is to remove excess body fat itself that is the causative substance.
  • lipid in tissues and blood Excessive accumulation of lipid in tissues and blood is the main causes of diverse metabolic syndrome with body weight gain. Abdominal fat increased by a high fat diet affects the body fat and sugar metabolism, and increases triglyceride levels in the blood. Increasing triglyceride levels in the blood causes the accumulation of triglycerides in various tissues. Hepatic disease can be mentioned as a representative metabolic syndrome in which lipid accumulated in tissues is a direct cause of the disease. The accumulation of triglycerides resulting in more 5% of hepatocytes is defined as hepatic steatosis, which can develop into steatohepatitis [7].
  • Lipophagy system is known to function to remove lipid droplets accumulated in cells, and Mark J. Czaja and Ana Maria Cuervo conducted a joint research project and as a result, published in the 2009 Nature Journal that the lipid droplets accumulated in cells are removed by the action of lipophagy. Thereafter, studies on its mechanism and activation method are actively underway. Therefore, if the lipophagy process can be controlled by a technical method, it can be used as an effective therapeutic agent that can replace existing anti-obesity agents that prevent the lipid accumulation through regulation of feeding patterns and energy metabolism.
  • the present invention provides a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • R 1 is -L 1 -(phenyl)
  • R 2 is hydrogen, or -L 2 -(phenyl),
  • L 1 is C 1-5 alkylene
  • L 2 is C 1-5 alkylene
  • L 1 is a linear C 1-5 alkylene. More preferably, L 1 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.
  • L 2 is a linear C 1-5 alkylene. More preferably, L 2 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 —.
  • R 1 is —CH 2 -(phenyl)
  • R 2 is hydrogen, —CH 2 CH 2 -(phenyl), —CH 2 CH 2 CH 2 -(phenyl), or —CH 2 CH 2 CH 2 CH 2 -(phenyl).
  • R 1 and R 2 are equal to each other. More preferably, R 1 and R 2 are —CH 2 CH 2 -(phenyl), —CH 2 CH 2 CH 2 -(phenyl), or —CH 2 CH 2 CH 2 CH 2 -(phenyl).
  • the compounds represented by Chemical Formula 1 above may be used in the form of pharmaceutically acceptable salts; and as the salt, an acid addition salt formed in the form of a pharmaceutically acceptable free acid is useful.
  • the acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, azilic acid or phosphorous acid, non-toxic organic acids such as aliphatic mono- or di-carboxylate, phenyl-substituted alkanoates, hydroxyalkanoates or alkanedioates, aromatic acids, aliphatic or aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid.
  • inorganic acids such as hydrochloric acid, nitric acid, phospho
  • salts as described above include sulfate, pyrosulfate, bisulfate, sulfide, bisulfide, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, methaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dionate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, di nitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulf
  • the acid addition salt may be prepared by a conventional method.
  • the acid addition salt may be prepared by dissolving the amino acid derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, or the like, adding an organic or inorganic acid, and filtering and drying the produced precipitates, or alternatively distilling a solvent and an excess acid under reduced pressure, followed by drying or crystallization in the presence of an organic solvent.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • An alkaline metal or alkaline earth metal salt may be prepared, for example, by dissolving the compound in an excessive amount of an alkaline metal hydroxide or alkaline earth metal hydroxide solution, filtering non-dissolved compound salts, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt.
  • a salt corresponding thereto may be obtained by reacting the alkaline metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • the present invention includes not only the compound expressed in Chemical Formula 1 and the pharmaceutically acceptable salt thereof but also all of the solvates, optical isomers, hydrates, and the like, capable of being prepared from therefrom.
  • the present invention provides, for example, a process for preparing a compound represented by Chemical Formula 1 as shown in the following Reaction Scheme 1.
  • R 1 and R 2 are the same as defined above.
  • the reaction is a reaction for preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 1-1 and the compound represented by Chemical Formula 1-2, and is substantially composed of two steps. Specifically, the compound represented by Chemical Formula 1-1 is reacted with the compound represented by Chemical Formula 1-2 to prepare an imine compound, wheic which is then reduced to prepare the compound represented by Chemical Formula 1.
  • the solvent that can be used in the above reaction may be water, ethanol, tetrahydrofuran, dichloromethane, toluene, or acetonitrile, without being restricted thereto.
  • the reaction temperature is not particularly limited, but the reaction may be performed at 10° C. to 90° C., preferably 10° C. to 30° C. or 60° C. to 80° C.
  • the reducing agent is not particularly limited, and NaBH 4 may be used as an example.
  • a purification step may be included as needed.
  • the present invention provides a pharmaceutical composition for preventing or treating obesity or metabolic syndrome, comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
  • the compounds according to the present invention selectively decomposes lipid droplets accumulated excessively in adipocytes to reduce the size of accumulated lipid droplets, through Oil Red-O staining method. Further, as confirmed in the weight loss effect of the compound of the present invention in high-fat diet-fed mice, when injected intraperitoneally in high-fat diet induced obese mice, a statistically significant level of weight loss effect was confirmed compared to control drug-treated mice.
  • the compounds according to the present invention can selectively reduce or eliminate only adipocytes which have been excessively accumulated, that it, adipocytes which may be a cause for inducing diseases. Therefore, the compounds according to the present invention can be an effective alternative to previous drugs that are concerned about the occurrence of side effects by inducing an increase in energy consumption or a change of feeding style through changes in metabolic processes.
  • Examples of the metabolic syndromes include any one selected from the group consisting of myocardial infarction, arteriosclerosis, hyperlipidemia, hypertension, cerebral infarction, cerebral hemorrhage, fatty liver, and type 2 diabetes mellitus.
  • Such a metabolic syndrome acts as the major cause of obesity due to the decrease in physical activity, in addition to the intake of high-fat diets, and is a disease accompanied by metabolic abnormalities such as increased body fat, blood pressure elevation, and blood lipid abnormality.
  • the treatment or prevention of obesity through the removal of excessive accumulated body fat may be effective in improving the prognosis of the metabolic syndrome.
  • prevention refers to all the activities of inhibiting or delaying occurrence, spread or recurrence of the above-mentioned diseases by the administration of the pharmaceutical composition of the present invention
  • treatment refers to all the activities of improving or changing the symptoms of the above diseases for the better by the administration of the pharmaceutical composition of the present invention.
  • the pharmaceutical compositions according to the present invention may be formulated in an oral administration form or a parenteral administration form according to standard pharmaceutical practice.
  • the dosage forms may contain additives such as pharmaceutically acceptable carrier, adjuvant, or diluents, in addition to the active ingredient.
  • the suitable carrier may include, for example, a saline solution, polyethyleneglycol, ethanol, vegetable oil and isopropyl myristate, and the like, the diluents may include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, celluolose and/or glycine, and the like, without being limited thereto.
  • the compounds of the present invention may be dissolved in oil commonly used for preparing an injection solution, propyleneglycol or other solvents. And, for local action, the compound of the present invention may be formulated into an ointment or cream. And, for local administration, the compound of the present invention may be formulated into ointment, gel or cream.
  • Preferable administration amount of the compound of the present invention is varied according to the condition and body weight of a patient, the severity of disease, the form of drug, administration route and period, but may be appropriately selected by a person of ordinary skill in the art. However, in order to achieve preferable effect, it is preferable to administer the compound represented by Chemical Formula 1 according to the present invention in an amount of 0.0001 to 100 mg/kg (body weight), preferably 0.001 to 100 mg/kg (body weight) per day. It may be administered orally or parenterally once a day or in divided doses.
  • the pharmaceutical composition according to the present invention may contain 0.001 to 99 wt %, preferably 0.01 to 60 wt % of the compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention may be administered to mammals including rat, mouse, domestic animals and human being through various routes. All modes of administration may be expected, and for example, it may be administered orally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine or intracerbroventricular injection.
  • the compound or a pharmaceutically acceptable salt thereof according to the present invention can be effectively used for preventing or treating obesity or metabolic syndrome.
  • FIG. 1 and FIG. 2 show results confirming the effects of decreasing the lipid droplet size in 3T3-L1 adipocytes and Hep G2 hepatocytes by the compounds of the present invention through Oil Red O staining
  • FIG. 3 shows the results confirming the effects of decreasing the lipid droplet size and number in 3T3-L1 adipocytes by the compounds of the present invention through BODIPY staining.
  • FIG. 4 shows the results confirming a phenomenon in which the compounds of the present invention activate the lipophagy process in 3T3-L1 adipocytes ( FIG. 4A ) and Hep G2 hepatocytes ( FIG. 4B ) and the activated lipophagy process decreases the size and number of lipid droplets accumulated in cells, through the immunofluorescence staining.
  • FIG. 5 shows the results confirming that treatment of the compounds of the present invention and Bafilomycin as an inhibitor of the action of lipophagy together did not result in removal of lipid droplets, in order to verify that the compounds of the present invention had removed the lipid droplets through the lipophagy process.
  • FIG. 6 shows the results confirming that in order to confirm the anti-obesity effect of the compounds of the present invention at the living body level, obesity was induced in wild-type mice via high-fat diets, and the body weight and abdominal adipose tissue size were reduced after treatment of the placebo and the compounds of the present invention.
  • FIG. 7 shows the result recording the changes in body weight weekly by the treatment of the placebo and the compound of the present invention.
  • FIG. 8 is a graph showing the measurement results of the weight of each tissue in order to confirm that the weight loss effect exhibited by the treatment of the compound of the present invention was caused by a decrease in the adipose tissue weight.
  • FIG. 9 is a graph showing the results of comparison of the weights of adipose tissues reduced by the compounds of the present invention.
  • FIG. 10 is a photograph comparing the actual appearance of each tissue extracted to confirm that the weight of the adipose tissue alone has reduced.
  • the left side was one treated with the vehicle, and the right side was one treated with the compound of the present invention.
  • FIG. 11 is a graph showing the percentage of the body weight reduced through the compounds of the present invention.
  • the results of measurement of the body height was shown to compare the degree of development during the administration period.
  • the results of surveying feed intake were shown.
  • FIG. 12 shows the results of the items that have examined blood samples taken from the placebo-treated mice and the compound-administered mice in order to understand that the weight loss caused by the compounds of the present invention has an effect on blood lipid components, blood glucose and pathological conditions of the tissue.
  • FIG. 13 shows the results of observation of mouse adipose tissues through HnE staining in order to confirm the removal effect of lipid droplets accumulated in the tissues by the compounds of the present invention.
  • FIG. 14 shows the result of observation of mouse adipose tissue through HnE staining in order to confirm that the size of adipocytes was reduced by the compound of the present invention.
  • FIG. 15 shows the results confirming the improvement of the expression of LC3 protein as a marker of lipophagy activity through tissue immunochemical staining in order to confirm that the weight loss and the lipid droplet-reducing effects exhibited by the compounds of the present invention were caused by the action of lipophagy.
  • FIG. 16 shows the results of observation of the expression patterns of macrophages, which are inflammatory cells, through tissue immunochemical staining in order to observe the relaxation effect of the compounds of the present invention against inflammatory symptoms in hepatic tissues caused by excessive accumulation of lipid droplets.
  • 2-(3,4-Diphenethoxybenzylamino)ethanol (1.0 g, 2.75 mmol) prepared in the previous step 2 was dissolved in methanol (25 mL) and HCl gas was introduced for 1 hour. The mixture was further stirred for 2 hours and evaporated to about 1 mL, and then hexane was added to prepare a solid, which was then filtered and dried to give the final compound 2-(3,4-diphenethoxybenzylamino)ethanol hydrochloride (720 mg, 65%).
  • 3,4-Dihydroxybenzaldehyde 500 mg, 3.62 mmol was diluted with DMF (10 mL), and anhydrous K 2 CO 3 (1.5 g, 10.86 mmol) and (3-bromopropyl)benzene (1.2 mL, 7.96 mmol) were slowly added in this order.
  • the mixture was heated to 80° C. and stirred for 2 hours and then cooled to room temperature.
  • the mixture was partitioned between water (50 mL) and ether (50 mL). The organic layer was separated and the water was extracted with ether (3 ⁇ 50 mL). The extracted organic layer was washed with water (2 ⁇ 50 mL) and saturated with aqueous NaCl solution (50 mL).
  • 2-(3,4-bis(3-phenylpropoxy)benzylamino)ethanol (1.0 g, 2.75 mmol) prepared in the previous step 2 was dissolved in methanol (25 mL) and HCl gas was introduced for 1 hour. The mixture was further stirred for 2 hours and evaporated to about 1 mL, and then hexane was added to prepare a solid, which was then filtered and dried to give 2-(3,4-bis(3-phenylpropoxy)-benzylamino)ethanol hydrochloride (720 mg, 65%).
  • 2-(4-(benzyloxy)-3-phenethoxybenzylamino)ethanol (1.0 g, 2.75 mmol) prepared in the previous step 2 was dissolved in methanol (25 mL) and HCl gas was introduced for 1 hour. The mixture was stirred for 2 hours and evaporated to about 1 mL, and then hexane was added to prepare a solid, which was then filtered and dried to give 2-(4-(benzyloxy)-3-phenethoxybenzylamino)ethanol hydrochloride (720 mg, 65%).
  • 2-(4-(benzyloxy)-3-(3-phenylpropoxy)benzylamino)ethanol (1.0 g, 2.75 mmol) prepared in the previous step 2 was dissolved in methanol (25 mL) and HCl gas was introduced for 1 hour. The mixture was further stirred for 2 hours and evaporated to about 1 mL, and then hexane was added to prepare a solid, which was then filtered and dried to give 2-(4-(benzyloxy)-3-(3-phenylpropoxy)benzylamino)ethanol hydrochloride (720 mg, 65%).
  • 3T3-L1 preadipocytes were purchased from Korean Cell Line Bank, and cultured and maintained in newborn calf serum (NCS, Invitrogen Corporation, Auckland, New Zealand) and high-glucose DMEM (high glucose Dulbecco's modified Eagle's Medium, Sigma Co., St. Louis, Mo., USA).
  • 3T3-L1 For adipocyte differentiation, 3T3-L1 with a concentration of 100,000 cells/ml were grown to confluence with 10% fetal bovine serum (FBS) and high-glucose DMEM for 2 days, then cultured in 10% FBS/high-glucose DMEM containing 0.5 mM IBMX (3-isobytyl-1-methyl xanthine), 0.5 ⁇ M dexamethasone and 5 ⁇ g/ml insulin (MDI) for 2 days, and further cultured in 10% FBS/high-glucose DMEM containing only 5 ⁇ g/ml insulin(1) for 4 days, following by again culturing in 10% FBS/high-glucose DMEM alone for another 6 days.
  • FBS fetal bovine serum
  • MDI ⁇ g/ml insulin
  • the cells were cultured for a total of 10 days to differentiate into adipocytes. After confluent culture, the cells were treated with the compounds at a concentration of 10 ⁇ M each time the medium was changed. On day 10 after differentiation, the cultured cells were fixed with 4% paraformaldehyde and then stained with Oil Red O staining solution. The Oil Red O staining was performed by diluting 0.5 g/200 ml isopropanol stock solution with 60% distilled water, and observed through a microscope at 400 ⁇ magnification. The results are illustrated in FIG. 1 .
  • a red circular structure represents a lipid droplet accumulated in cells.
  • FIG. 1 it shows that the size and number of lipid droplets were reduced by the treatment of the compounds according to the present invention. Therefore, it can be confirmed that the compound according to the present invention is effective for removing lipid droplets in 3T3-L1 preadipocytes.
  • Hep G2 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum (Hyclone, USA), 100 U/mL penicillin and 100 mg/mL streptomycin (Hyclone, USA).
  • DMEM medium supplemented with 10% fetal bovine serum (Hyclone, USA), 100 U/mL penicillin and 100 mg/mL streptomycin (Hyclone, USA).
  • the medium was replaced with DMEM medium containing 1 mM oleic acid and 0.5 mM palmitic acid to induce intracellular lipid accumulation, and the cells were cultured for 24 hours.
  • the medium was then replaced with DMEM medium containing 10 ⁇ M of each compound synthesized through the present invention and the cells were further cultured for 24 hours.
  • the cells were fixed with 4% paraformaldehyde for 10 minutes and washed three times with PBS.
  • the cells were then rinsed with 60% isopropanol and then stained with diluted Oil Red O solution (stock solution, 3 mg/mL in isopropanol, working solution, 60% Oil Red O stock solution diluted in water) for 1 hour.
  • Oil Red O staining was performed by diluting 0.5 g/200 ml isopropanol stock solution with 60% distilled water, and observed through a microscope at a 400 ⁇ magnification. The results are illustrated in FIG. 2 .
  • a red circular structure represents a lipid droplet accumulated in cells.
  • FIG. 2 it shows that the size and number of lipid droplets were reduced by the treatment of the compounds according to the present invention. Therefore, it can be confirmed that the compound according to the present invention had an effect of removing lipid droplets in Hep G2 hepatocytes.
  • 3T3-L1 preadipocytes were purchased from Korean Cell Line Bank, and cultured and maintained in newborn calf serum (NCS, Invitrogen Corporation, Auckland, New Zealand) and high-glucose DMEM (high glucose Dulbecco's modified Eagle's Medium, Sigma Co., St. Louis, Mo., USA).
  • 3T3-L1 For adipocyte differentiation, 3T3-L1 with a concentration of 100,000 cells/ml were grown to confluence with 10% fetal bovine serum (FBS) and high-glucose DMEM for 2 days, then cultured in 10% FBS/high-glucose DMEM containing 0.5 mM IBMX (3-isobytyl-1-methyl xanthine), 0.5 ⁇ M dexamethasone and 5 ⁇ g/ml insulin (MDI) for 2 days, and further cultured in 10% FBS/high-glucose DMEM containing only 5 ⁇ g/ml insulin(I) for 4 days, followed by again culturing in 10% FBS/high-glucose DMEM for another 6 days.
  • FBS fetal bovine serum
  • MDI 0.5 ⁇ M dexamethasone
  • MDI 5 ⁇ g/ml insulin
  • the cells were cultured for a total of 10 days to differentiate into adipocytes. After confluent culture, the cells were treated with the compounds at a concentration of 10 ⁇ M each time the medium was changed. On day 10 after differentiation, the cultured cells were fixed with 4% paraformaldehyde and then lipid droplets were stained using BODIPY, a marker of lipid droplets, and the nuclei in cells were labeled through DAPI staining. The results are illustrated in FIG. 3 .
  • a green circular structure represents a lipid droplet accumulated in cells, which shows that the size and number of lipid droplets were reduced by the treatment of the compounds according to the present invention. Therefore, it was confirmed that the compound of the present invention is effective for removing lipid droplets in preadipocytes.
  • 3T3-L1 preadipocytes were purchased from Korean Cell Line Bank, and cultured and maintained in newborn calf serum (NCS, Invitrogen Corporation, Auckland, New Zealand) and high-glucose DMEM (high glucose Dulbecco's modified Eagle's Medium, Sigma Co., St. Louis, Mo., USA).
  • adipocyte differentiation 3T3-L1 with a concentration of 100,000 cells/ml were grown to confluence with 10% fetal bovine serum (FBS) and high glucose DMEM for 2 days, then cultured in 10% FBS/high-glucose DMEM containing 0.5 mM IBMX (3-isobytyl-1-methyl xanthine), 0.5 ⁇ M dexamethasone and 5 ⁇ g/ml insulin (MDI) for 2 days, and further cultured in 10% FBS/high-glucose DMEM containing only 5 ⁇ g/ml insulin(I) for 4 days, followed by again culturing in 10% FBS/high-glucose DMEM alone for another 6 days.
  • FBS fetal bovine serum
  • MDI 0.5 ⁇ M dexamethasone
  • MDI 5 ⁇ g/ml insulin
  • the cells were cultured for a total of 10 days to differentiate into adipocytes. After confluent culture, the cells were treated with
  • Hep G2 hepatocytes were inoculated into a 24 well cell culture plate containing a cover slip, cultured in a DMEM medium containing 1 mM of oleic acid and 0.5 mM of palmitic acid for 24 hours to induce lipid accumulation, which was then treated with 10 ⁇ M of each compound and incubated for another 24 hours.
  • each cell was then washed twice with PBS solution, fixed with 4% paraformaldehyde solution for 15 minutes, and blocked in PBS solution containing 2% BSA for 1 hour. After blocking was completed, it was subjected to a primary antibody reaction.
  • the primary antibody reaction was performed using LC3 rabbit polyclonal antibody (1:300, Sigma-Aldrich, USA) overnight at 4° C. After completion of the primary antibody reaction, cover slips were washed twice with PBS, and a secondary antibody (1:500, goat anti rabbit Alexa flour 555, Thermo Fisher, US) was reacted at room temperature for 1 hour.
  • the cells were washed twice with PBS, and then BODIPY 493/503 was reacted at room temperature for 10 minutes and mounted on a slide glass using a mounting medium.
  • the stained cells were photographed using a confocal microscope, and the results are illustrated in FIG. 4 .
  • a green circular structure represents a lipid droplet accumulated in cells, and it can be confirmed that the lipid droplets were accumulated in 3T3-L1 preadipocytes during the differentiation process into the adipocytes.
  • red stained LC3 which is a marker capable of tracking the level of lipophagy activity, was increased as compared with cell treated with placebo.
  • LC3 red stained LC3
  • the green circular structures represent lipid droplets accumulated in cells, and it can be confirmed that by treating oleic acid and palmitic acid, which are one type of fatty acids, the accumulation of lipid droplets was induced as compared with the control group treated with BSA.
  • the red-stained LC3 which is a marker capable of tracking the level of the lipophagy activity, was increased.
  • LC3, a marker of lipophagy is located on the surface of lipid droplets through images obtained by superimposing an image of green-stained lipid droplets and an image of red-stained LC3.
  • the red circular structures represent lipid droplets, which show that the lipid droplets reduced by the compounds of the present invention did not decrease in response to the treatment of bafilomycin.
  • the reduction effect of the number and size of lipid droplets did not appear when treated with the compound according to the present invention, it could be seen that the effect of removing lipid droplets by the present compound was caused by the action of lipophagy.
  • wild-type C57BL6 mice (6 weeks old) were supplied from Medical Center for Experimental Animal Resource Development, Seoul National University and divided into general feed intake group (LFD) and high calorie diet intake group (HFD) through random assignment.
  • LFD general feed intake group
  • HFD high calorie diet intake group
  • the high-fat intake group was again divided into a group treated with placebo and a group treated with the compound of the present invention, and divided into a total of three groups to conduct obesity induction and compound treatment at the same time. As a result, it was analyzed whether the compound could effectively remove the fat inflowing excessively and thus prevent obesity.
  • mice that had been supplied were allowed to freely consume water after a week of adaptation period in the rearing cage.
  • high-fat diets protein: 10%, carbohydrate: 30%
  • normal diets protein: 18.8%, carbohydrate: 63.9%) in which 17.2% of the total calories (3.8 kcal/g) was composed of fat
  • the compound of the present invention was dissolved in DMSO at 1 ⁇ L/mg (v/w), then diluted with PBS, and administered intraperitoneally three times per week at a concentration of 20 ⁇ g/g body weight of mice.
  • mice body weights were measured three times a week.
  • euthanasia was induced by excessive supply of CO 2 after 24 hours including an 8 hour fasting period after the final administration, and then laparotomy was performed, and changes in body fat were observed.
  • the results of the body fat removing effect, the change in body weight, the difference in feed intake and the difference in height due to the administration of the high fat diets and the compound according to the present invention are illustrated in FIGS. 6, 7, 8, 9, 10 and 11 , respectively.
  • the hepatic tissues of the mice of the previous Experimental Example 5 were observed through HnE staining method, and the results are illustrated in FIG. 13 .
  • the white circular structures indicated by yellow arrows represent lipid droplets, from which it can be seen that the size and number of lipid droplets accumulated in hepatocytes were decreased by the treatment of the compound of the present invention.
  • the adipose tissue of the mouse of the previous Experimental Example 5 was observed through the HnE staining method, and the results are illustrated in FIG. 14 .
  • the structures indicated by blue arrows and black and yellow dots represent adipocytes in adipose tissue, from which it can be seen that the size of the adipocytes was reduced by the treatment of the compounds.
  • mice of the previous Experimental Example 5 were dissected to analyze whether reduction or removal of lipid droplets in liver has occurred through immunohistochemical staining method.
  • the staining solution used for immunohistochemical staining was purchased from Sigma-Aldrich. All procedures were performed on 5- ⁇ m sections of liver tissue embedded in paraffin at room temperature. Antigen regeneration was performed on formalin fixed tissue for 15 minutes at 100° C. in a water bath prior to immunohistochemical staining. Endogenous peroxidase activity was blocked by hydrogen peroxide. Primary antibodies were detected with HRP-conjugated polymer and developed by DAB. Slides were then counterstained with hematoxylin, and subjected to multi-stage alcohol dehydration and mounted with a mounting medium.
  • FIG. 15 The results are illustrated in FIG. 15 .
  • LC3 protein stained in brown color on the surface of the lipid droplets was disposed in the area indicated by the yellow square. From this, it can be seen that the removal of lipid droplets was directly caused by the action of lipophagy occurring on the surface of the lipid droplets.
  • FIG. 16 the brown-labeled cells represent macrophages, from which it could be seen that macrophages accumulated in hepatic tissues were decreased by the treatment of the compound of the present invention. Thereby, it can be seen that macrophages accumulated in hepatic tissues were decreased by the treatment of the compound of the present invention.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013022919A1 (en) * 2011-08-08 2013-02-14 University Of Pittsburgh - Of The Commonwealth System Of Higher Education P62-zz chemical inhibitor

Family Cites Families (8)

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Publication number Priority date Publication date Assignee Title
AU666133B2 (en) 1991-10-04 1996-02-01 Taisho Pharmaceutical Co., Ltd. Alkoxyphenylalkylamine derivative
NO179246C (no) 1991-11-20 1996-09-04 Sankyo Co Aromatiske amino-alkoholderivater og mellomprodukter til fremstilling derav
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US6476075B1 (en) * 1999-09-23 2002-11-05 G.D. Searle & Co. Use of substituted N, N-bis-benzyl aminoalcohol compounds inhibiting cholesteryl ester transfer protein activity
KR20090035707A (ko) 2006-07-19 2009-04-10 더 오하이오 스테이트 유니버시티 리서치 파운데이션 선택적인 안드로겐 수용체 모듈레이터, 그 유사체와 유도체, 및 그의 용도
KR101594168B1 (ko) 2013-10-02 2016-02-15 서울대학교산학협력단 p62의 ZZ 영역에 의해 매개되는 자가포식 조절 방법 및 그 용도
AU2016274576A1 (en) 2015-06-11 2017-12-21 University Of Pittsburgh - Of The Commonwealth System Of Higher Education p62-ZZ chemical inhibitor
KR101731908B1 (ko) * 2015-08-18 2017-05-11 서울대학교산학협력단 p62 ZZ 도메인에 결합하는 리간드 또는 아르기닌화된 BiP에 의해 매개되는 오토파지 활성을 통한 신경변성 질환 예방 및 치료

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* Cited by examiner, † Cited by third party
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WO2013022919A1 (en) * 2011-08-08 2013-02-14 University Of Pittsburgh - Of The Commonwealth System Of Higher Education P62-zz chemical inhibitor

Cited By (1)

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US11981618B2 (en) 2018-07-24 2024-05-14 Autotac Inc. P62 ligand compound, and composition for preventing, ameliorating or treating proteinopathies comprising the same

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